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Loss-Of-Function Mutations in ATP6AP1 and ATP6AP2 in Granular Cell Tumors

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Loss-Of-Function Mutations in ATP6AP1 and ATP6AP2 in Granular Cell Tumors Thomas Jefferson University Jefferson Digital Commons Department of Pathology, Anatomy, and Cell Department of Pathology, Anatomy, and Cell Biology Faculty Papers Biology 12-1-2018 Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors. Fresia Pareja Memorial Sloan Kettering Cancer Center Alissa H. Brandes Memorial Sloan Kettering Cancer Center Thais Basili Memorial Sloan Kettering Cancer Center Pier Selenica Memorial Sloan Kettering Cancer Center Felipe C. Geyer Memorial Sloan Kettering Cancer Center See next page for additional authors Let us know how access to this document benefits ouy Follow this and additional works at: https://jdc.jefferson.edu/pacbfp Part of the Pathology Commons Recommended Citation Pareja, Fresia; Brandes, Alissa H.; Basili, Thais; Selenica, Pier; Geyer, Felipe C.; Fan, Dan; Da Cruz Paula, Arnaud; Kumar, Rahul; Brown, David N.; Gularte-Mérida, Rodrigo; Alemar, Barbara; Bi, Rui; Lim, Raymond S.; de Bruijn, Ino; Fujisawa, Sho; Gardner, Rui; Feng, Elvin; Li, Anqi; da Silva, Edaise M.; Lozada, John R.; Blecua, Pedro; Cohen-Gould, Leona; Jungbluth, Achim A.; Rakha, Emad A.; Ellis, Ian O.; Edelweiss, Maria I.A.; Palazzo, Juan P.; Norton, Larry; Hollmann, Travis; Edelweiss, Marcia; Rubin, Brian P.; Weigelt, Britta; and Reis-Filho, Jorge S., "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors." (2018). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 241. https://jdc.jefferson.edu/pacbfp/241 Authors Fresia Pareja, Alissa H. Brandes, Thais Basili, Pier Selenica, Felipe C. Geyer, Dan Fan, Arnaud Da Cruz Paula, Rahul Kumar, David N. Brown, Rodrigo Gularte-Mérida, Barbara Alemar, Rui Bi, Raymond S. Lim, Ino de Bruijn, Sho Fujisawa, Rui Gardner, Elvin Feng, Anqi Li, Edaise M. da Silva, John R. Lozada, Pedro Blecua, Leona Cohen-Gould, Achim A. Jungbluth, Emad A. Rakha, Ian O. Ellis, Maria I.A. Edelweiss, Juan P. Palazzo, Larry Norton, Travis Hollmann, Marcia Edelweiss, Brian P. Rubin, Britta Weigelt, and Jorge S. Reis-Filho This article is available at Jefferson Digital Commons: https://jdc.jefferson.edu/pacbfp/241 ARTICLE DOI: 10.1038/s41467-018-05886-y OPEN Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors Fresia Pareja1, Alissa H. Brandes1, Thais Basili1, Pier Selenica1, Felipe C. Geyer1, Dan Fan1, Arnaud Da Cruz Paula1, Rahul Kumar1, David N. Brown1, Rodrigo Gularte-Mérida1, Barbara Alemar1,2, Rui Bi1,3, Raymond S. Lim1, Ino de Bruijn1, Sho Fujisawa4, Rui Gardner5, Elvin Feng4, Anqi Li1,3, Edaise M. da Silva1, John R. Lozada 1, Pedro Blecua6, Leona Cohen-Gould7, Achim A. Jungbluth1, Emad A. Rakha8, Ian O. Ellis8, Maria I.A. Edelweiss9, Juan Palazzo10, Larry Norton11, Travis Hollmann1, Marcia Edelweiss1, Brian P. Rubin12, Britta Weigelt1 & Jorge S. Reis-Filho1 1234567890():,; Granular cell tumors (GCTs) are rare tumors that can arise in multiple anatomical locations, and are characterized by abundant intracytoplasmic granules. The genetic drivers of GCTs are currently unknown. Here, we apply whole-exome sequencing and targeted sequencing analysis to reveal mutually exclusive, clonal, inactivating somatic mutations in the endosomal pH regulators ATP6AP1 or ATP6AP2 in 72% of GCTs. Silencing of these genes in vitro results in impaired vesicle acidification, redistribution of endosomal compartments, and accumula- tion of intracytoplasmic granules, recapitulating the cardinal phenotypic characteristics of GCTs and providing a novel genotypic–phenotypic correlation. In addition, depletion of ATP6AP1 or ATP6AP2 results in the acquisition of oncogenic properties. Our results demonstrate that inactivating mutations of ATP6AP1 and ATP6AP2 are likely oncogenic dri- vers of GCTs and underpin the genesis of the intracytoplasmic granules that characterize them, providing a genetic link between endosomal pH regulation and tumorigenesis. 1 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065 NY, USA. 2 Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre 91501-970, Brazil. 3 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China. 4 Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York 10065 NY, USA. 5 Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York 10065 NY, USA. 6 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York 10065 NY, USA. 7 Department of Biochemistry, Weill Cornell Medical College, New York 10065 NY, USA. 8 Department of Pathology, University of Nottingham, Nottingham NG7 2RD, UK. 9 Hospital de Clínicas, Federal University of Rio Grande do Sul, Porto Alegre 90035-903, Brazil. 10 Department of Pathology, Jefferson Medical College, Philadelphia 19107 PA, USA. 11 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York 10065 NY, USA. 12 Departments of Pathology and Cancer Biology, Robert J. Tomsich Pathology and Laboratory Medicine Institute and The Lerner Research Institute, Cleveland Clinic, Cleveland 44195 OH, USA. These authors contributed equally: Fresia Pareja, Alissa H. Brandes, Thais Basili. Correspondence and requests for materials should be addressed to B.W. (email: [email protected]) or to J.S.R-F. (email: reisfi[email protected]) NATURE COMMUNICATIONS | (2018) 9:3533 | DOI: 10.1038/s41467-018-05886-y | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-05886-y ranular cell tumors (GCTs) are uncommon neoplasms Our study comprised a discovery cohort (n = 17) and a which can arise in multiple anatomical sites. These validation cohort (n = 65; Fig. 1). To determine whether GCTs G 1 tumors usually follow a benign course , but may occa- would be underpinned by a pathognomonic genetic alteration, we sionally exhibit an aggressive behavior with local and distant subjected the 17 GCTs of the discovery cohort to WES and 11 recurrences1–3. GCTs are characterized by abundant intracyto- GCTs to RNA sequencing, with 10 cases being subjected to both plasmic granules, whose nature and function remain unclear1. (Fig. 1, Supplementary Table 1). These analyses revealed a paucity The genetic landscape of GCTs and the mechanisms under- of CNAs (Supplementary Fig. 1a), no recurrently mutated known pinning the presence of their characteristic intracytoplasmic cancer genes, and no recurrent likely pathogenic fusion genes granules are currently unknown1. (Fig. 2a, Supplementary Table 2). Rather, WES analysis revealed There is a burgeoning body of evidence indicating that genetic recurrent, mutually exclusive, and clonal loss-of-function (i.e., analysis of rare cancer types may provide unique opportunities nonsense or frameshift) somatic mutations affecting ATP6AP1 or for the identification of novel cancer drivers4. A subset of rare ATP6AP2 in 12/17 of the GCTs analyzed (p = 0.041, CoMEt; tumors not uncommonly have simple genomes, with a paucity of Fig. 2a, Supplementary Fig. 1b, Supplementary Tables 3–4). All copy number alterations (CNAs) and somatic mutations, and are ATP6AP1 and ATP6AP2 somatic mutations identified by WES characterized by highly recurrent, specific, or even pathogno- were validated by Sanger sequencing (Supplementary Fig. 1c). To monic, somatic mutations, or fusion genes4. These tumors have validate our findings, we subjected 65 additional GCTs from the distinctive phenotypes and often arise in diverse anatomic loca- validation cohort to targeted massively parallel sequencing, which tions. Akin to these tumors, GCTs are rare, arise in different revealed mutually exclusive loss-of-function mutations (i.e., anatomic locations, and display peculiar morphologic features; nonsense, frameshift, or splice-site) affecting ATP6AP1 and hence, we posited that they could also be underpinned by a highly ATP6AP2 in 36/65 and 6/65 cases, respectively (p = 0.0028, recurrent genetic alteration. CoMEt; Figs. 1 and 2b, Supplementary Table 1). In addition, 5/65 Here, through a whole-exome sequencing (WES) and targeted GCTs harbored ATP6AP1 in-frame indels affecting evolutionarily sequencing analysis of GCTs, we uncovered highly recurrent and conserved residues (Fig. 2b, Supplementary Fig. 1d). All mutually exclusive inactivating mutations targeting the endoso- ATP6AP1 and ATP6AP2 mutations identified by targeted mal pH regulators ATP6AP1 and ATP6AP2 in GCTs. In vitro sequencing (n = 47) were validated by Sanger sequencing and/ silencing of ATP6AP1 and ATP6AP2 in human Schwann cells or repeat targeted capture sequencing analysis (Fig. 1a and and epithelial cells resulted in the accumulation of intracyto- Supplementary Table 1). In total, 72% (59/82) of the GCTs plasmic granules that are ultra-structurally and phenotypically analyzed here harbored likely inactivating somatic mutations in similar to those of human GCTs, altered endosomal acidification ATP6AP1 or ATP6AP2. Of note, no differences in histologic and oncogenic properties, thereby establishing a novel features (Supplementary Table 5) or anatomical site (Fig. 2c) of genotypic–phenotypic correlation. GCTs according to the ATP6AP1/ATP6AP2 mutational status were observed. Results Recurrent ATP6AP1 and ATP6AP2 somatic mutations in ATP6AP1 and ATP6AP2 inactivating mutations are expressed. GCTs. GCTs were retrieved from the authors’ institutions, fol- ATP6AP1 and ATP6AP2 map to Xq28 and Xp11.4, respectively. lowing the approval of this study by the local research ethics Therefore, a single inactivating mutation in either gene targeting committees or institutional
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